Nuclear Halogenopyrazines from Pyrazinamines

The conversion of (primary) pyrazinamines into the corresponding halogenopyrazines by one-pot diazotization and treatment with halides has proven reasonably satisfactory for making some chloro-, bromo-, or fluoropyrazines to date, iodopyrazines 

3-Amino-2-pyrazinecarbonitrile (56, R = NH2) gave 3-chloro-2-pyrazinecar-bonitrile (56, R = Cl) (NaNOz, HC1. NaCl, 0 20°C, 3 h 29%).262 

Methyl 3-amino- (59, R = NH2) gave methyl 3-bromo-6-chloro-5-(4-methylpiperazin-l-yl)-2-pyrazinecarboxylate (59, R = Br) (NaN02, Br2— HBr—AcOH—H20, 5°C, 30 min 47%).645 

6-Dichloro-3-nitro-2-pyrazinamine (60, R = NH2) gave 2-bromo-5,6-dichloro-3-nitropyrazine (60, R = Br) (Bu CH2ONO, excess CHBr3, reflux, 8 h then more Bu CH2ONO J, reflux, 10 h —50%, crude product mechanism ).1313 

5-Phenyl-2-pyrazinamine (61, R = NH2) gave 2-fluoro-5-phenylpyrazine (61, R = F) (NaN02, HBF4, H20, -5 - 20°C, 2.5 h %) 1457 2-fluoropyrazine 1-oxide (17%) was made somewhat similarly.276 

5-Benzyloxy-3-hydroxymethyl-6-isobutyl-2-pyrazinamine 1-oxide (57, R = CH2OH) gave 2-benzyloxy-5-chloro-6-hydroxymethyl-3-isobutylpyrazine 4-oxide (58, R = ( 111 )11) (Bu CHjONO, CuCl—CuCli, N2, MeCN, 20°C, 30 min 75%) and methyl 3-amino-6-benzyloxy-5-isobutyl-2-pyrazinecar-boxylate 4-oxide (57, R = CO2Me) gave methyl 6-benzyloxy-3-chloro-5-isobutyl-2-pyrazinecarboxylate 4-oxide (58, R = CO2Me) (likewise but 90 min 61%)  

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